Clarifying the causal contrast: An empirical example applying the prevalent new user study design.

PURPOSE: The prevalent new user design extends the active comparator new user design to include patients switching to a treatment of interest from a comparator. We examined the impact of adding "switchers" to incident new users on the estimated hazard ratio (HR) of hospitalized heart failure. METHODS: Using MarketScan claims data (2000-2014), we estimated HRs of hospitalized heart failure between patients initiating GLP-1 receptor agonists (GLP-1 RA) and sulfonylureas (SU). We considered three estimands: (1) the effect of incident new use; (2) the effect of switching; and (3) the effect of incident new use or switching, combining the two population. We used time-conditional propensity scores (TCPS) and time-stratified standardized morbidity ratio (SMR) weighting to adjust for confounding. RESULTS: We identified 76 179 GLP-1 RA new users, of which 12% were direct switchers (within 30 days) from SU. Among incident new users, GLP-1 RA was protective against heart failure (adjHRSMR = 0.74 [0.69, 0.80]). Among switchers, GLP-1 RA was not protective (adjHRSMR = 0.99 [0.83, 1.18]). Results in the combined population were largely driven by the incident new users, with GLP-1 RA having a protective effect (adjHRSMR = 0.77 [0.72, 0.83]). Results using TCPS were consistent with those estimated using SMR weighting. CONCLUSIONS: When analyses were conducted only among incident new users, GLP-1 RA had a protective effect. However, among switchers from SU to GLP-1 RA, the effect estimates substantially shifted toward the null. Combining patients with varying treatment histories can result in poor confounding control and camouflage important heterogeneity.

Characterizing Imbalance in the Tails of the Propensity Score Distribution.

Understanding characteristics of patients with propensity scores in the tails of the propensity score (PS) distribution has relevance for inverse-probability-of-treatment-weighted and PS-based estimation in observational studies. Here we outline a method for identifying variables most responsible for extreme propensity scores. The approach is illustrated in 3 scenarios: 1) a plasmode simulation of adult patients in the National Ambulatory Medical Care Survey (2011-2015) and 2) timing of dexamethasone initiation and 3) timing of remdesivir initiation in patients hospitalized for coronavirus disease 2019 from February 2020 through January 2021. PS models were fitted using relevant baseline covariates, and tails of the PS distribution were defined using asymmetric first and 99th percentiles. After fitting of the PS model in each original data set, values of each key covariate were permuted and model-agnostic variable importance measures were examined. Visualization and variable importance techniques were helpful in identifying variables most responsible for extreme propensity scores and may help identify individual characteristics that might make patients inappropriate for inclusion in a study (e.g., off-label use). Subsetting or restricting the study sample based on variables identified using this approach may help investigators avoid the need for trimming or overlap weights in studies.

Comparison of clinical outcomes in patients with schizophrenia following different long-acting injectable event-driven initiation strategies.

This retrospective study evaluated the benefit of following different long-acting injectable (LAI) initiation strategies based on the timing of behavioral and clinical events among Medicaid beneficiaries with schizophrenia. Adults with schizophrenia initiating oral antipsychotics (OAPs) after 12 months without antipsychotic use or schizophrenia-related inpatient/emergency room (ER) visits (index date) were identified. Patients were categorized into four event-driven LAI initiation strategy cohorts based on observed sequences of behavioral (i.e., OAP adherence) and clinical (i.e., schizophrenia-related inpatient/ER visits) events between index and LAI initiation or censoring-strategy #1: adherent to OAPs without schizophrenia-related inpatient/ER visits; strategy #2: nonadherent to OAPs without schizophrenia-related inpatient/ER visits; strategy #3: one schizophrenia-related inpatient/ER visit; strategy #4: ≥2 schizophrenia-related inpatient/ER visits. Clinical outcomes (i.e., all-cause inpatient/ER visits) were evaluated between OAP initiation and end of follow-up. Comparisons between LAI initiation strategy cohorts were conducted using a dynamic marginal structural model adjusting for baseline characteristics and time-varying confounders. Among 13,444 eligible patients, 13.1%, 53.6%, 15.7%, and 17.6% were following strategies #1-4, respectively; of these, 21.9%, 4.3%, 9.2%, and 6.5% started an LAI (the remaining were censored). Strategy #1 was associated with a greater clinical benefit, with 43%, 69%, and 80% fewer inpatient days (all p < 0.05); and 57%, 59%, and 79% fewer ER visits (all p < 0.01) vs strategies #2-4, respectively; the clinical benefit was also observed for strategy #2 vs #3-4. Therefore, starting an LAI prior to OAP nonadherence or occurrence of a schizophrenia-related inpatient/ER visit was associated with fewer all-cause inpatient days of inpatient stay and ER visits.

Real-world calibration and transportability of the Disease Recovery Evaluation and Modification (DREaM) randomized clinical trial in adult Medicaid beneficiaries with recent-onset schizophrenia.

BACKGROUND: The Disease Recovery Evaluation and Modification study (DREaM; NCT02431702) assessed the benefit of initiating paliperidone palmitate (PP), a long-acting injectable antipsychotic, in patients with recent-onset schizophrenia or schizophreniform disorder. OBJECTIVE: To determine whether reductions in psychiatric hospitalizations with early initiation of PP vs oral antipsychotic (OAP) therapy observed in a DREaM post hoc analysis are transportable to a real-world population of patients with recent-onset schizophrenia. METHODS: Patients enrolled in DREaM were randomized to receive OAP or PP for 9 months, after which OAP recipients were re-randomized to receive OAP or PP for another 9 months. We used this design to form treatment arms: OAP-OAP, OAP-PP, and PP-PP. Inclusion/exclusion criteria were used to identify a Medicaid Managed Care (MMC) OAP-treated cohort of 1,000 patients diagnosed with schizophrenia using IBM Truven databases from 2015 to 2019. The MMC cohort was combined with the subset of patients diagnosed with schizophrenia enrolled in DREaM from US sites (N = 45, 43, and 44 for OAP-OAP, OAP-PP, and PP-PP, respectively). Propensity scores for the MMC cohort were estimated using baseline variables identified via double-lasso regression. Estimated propensity scores were used to weight psychiatric hospitalizations in the DREaM OAP-OAP group and compared with observed MMC OAP cohort psychiatric hospitalizations. After the successful calibration of the DREaM OAP-OAP group, similar approaches were taken for the OAP-PP and PP-PP groups to transport DREaM effects to MMC data. RESULTS: Standardized mean differences in baseline covariates between DREaM treatment arms and MMC groups were substantially reduced after calibration. The 18-month cumulative numbers of psychiatric hospitalizations per patient (SE) were 0.83 (0.14) for the MMC cohort, 0.43 (0.14) for the unweighted OAP-OAP, and 0.80 (0.37) for the calibrated OAP-OAP. The difference between the calibrated OAP-OAP and MMC was not statistically significant (difference, 0.03 [95% CI = -0.67 to 0.81]), indicating successful calibration. The mean difference in 18-month cumulative psychiatric hospitalizations relative to the MMC cohort was -0.77 (95% CI = -1.08 to -0.47) for OAP-PP and -0.83 (95% CI = -1.15 to -0.60) for PP-PP. CONCLUSIONS: Our study demonstrates that results from the DREaM OAP-OAP group reflect psychiatric hospitalizations in a real-world population when calibrated using specific baseline characteristics. Transporting the DREaM effects, we find that using OAP-PP and PP-PP treatment strategies for patients with recent-onset schizophrenia in the MMC population could reduce psychiatric hospitalizations compared with the use of OAP. These findings, along with the potential reduction in associated costs, should be considered when assessing the value of PP formulations. DISCLOSURES: Dr Basu reports consulting fees through Salutis Consulting LLC related to this work. Dr Mavros is a former employee of the Janssen Pharmaceutical Companies of Johnson & Johnson, Inc, and holds stock in the company. Ms Benson, Dr Fu, Ms Patel, and Dr Brown are employees of Janssen Scientific Affairs, LLC, and hold stock in Johnson & Johnson. This research was funded by Janssen Scientific Affairs, LLC. The sponsor was involved in the study design; collection, analysis, and interpretation of data; and development and review of the manuscript. All authors had full access to the study data and take responsibility for data integrity and the accuracy of the analyses. All authors provided direction and comments on the manuscript, reviewed and approved the final version prior to submission, made the final decision about where to publish these data, and approved submission to this journal.

A mobile EEG study on the psychophysiological effects of walking and crowding in indoor and outdoor urban environments.

Environmental psychologists have established multiple psychological benefits of interaction with natural, compared to urban, environments on emotion, cognition, and attention. Yet, given the increasing urbanisation worldwide, it is equally important to understand how differences within different urban environments influence human psychological experience. We developed a laboratory experiment to examine the psychophysiological effects of the physical (outdoor or indoor) and social (crowded versus uncrowded) environment in healthy young adults, and to validate the use of mobile electroencephalography (EEG) and electrodermal activity (EDA) measurements during active walking. Participants (N = 42) were randomly assigned into a walking or a standing group, and watched six 1-min walk-through videos of green, urban indoor and urban outdoor environments, depicting high or low levels of social density. Self-reported emotional states show that green spaces is perceived as more calm and positive, and reduce attentional demands. Further, the outdoor urban space is perceived more positively than the indoor environment. These findings are consistent with earlier studies on the psychological benefits of nature and confirm the effectiveness of our paradigm and stimuli. In addition, we hypothesised that even short-term exposure to crowded scenes would have negative psychological effects. We found that crowded scenes evoked higher self-reported arousal, more negative self-reported valence, and recruited more cognitive and attentional resources. However, in walking participants, they evoked higher frontal alpha asymmetry, suggesting more positive affective responses. Furthermore, we found that using recent signal-processing methods, the EEG data produced a comparable signal-to-noise ratio between walking and standing, and that despite differences between walking and standing, skin-conductance also captured effectively psychophysiological responses to stimuli. These results suggest that emotional responses to visually presented stimuli can be measured effectively using mobile EEG and EDA in ambulatory settings, and that there is complex interaction between active walking, the social density of urban spaces, and direct and indirect affective responses to such environments.

Alternative analytic and matching approaches for the prevalent new-user design: A simulation study.

PURPOSE: To describe the creation of prevalent new user (PNU) cohorts and compare the relative bias and computational efficiency of several alternative analytic and matching approaches in PNU studies. METHODS: In a simulated cohort, we estimated the effect of a treatment of interest vs a comparator among those who switched to the treatment of interest using the originally proposed time-conditional propensity score (TCPS) matching, standardized morbidity ratio weighting (SMRW), disease risk scores (DRS), and several alternative propensity score matching approaches. For each analytic method, we compared the average RR (across 2000 replicates) to the known risk ratio (RR) of 1.00. RESULTS: SMRW and DRS yielded unbiased results (RR = 0.998 and 0.997, respectively). TCPS matching with replacement was also unbiased (RR = 0.999). TCPS matching without replacement was unbiased when matches were identified starting with patients with the shortest treatment history as initially proposed (RR = 0.999), but it resulted in very slight bias (RR = 0.983) when starting with patients with the longest treatment history. Similarly, creating a match pool without replacement starting with patients with the shortest treatment history yielded an unbiased estimate (RR = 0.997), but matching with the longest treatment history first resulted in substantial bias (RR = 0.903). The most biased strategy was matching after selecting one random comparator observation per individual that continued on the comparator (RR = 0.802). CONCLUSIONS: Multiple analytic methods can estimate treatment effects without bias in a PNU cohort. Still, researchers should be wary of introducing bias when selecting controls for complex matching strategies beyond the initially proposed TCPS.

Daratumumab Improves Depth of Response and Progression-free Survival in Transplant-ineligible, High-risk, Newly Diagnosed Multiple Myeloma.

BACKGROUND: Patients with high-risk, newly diagnosed multiple myeloma (HR-NDMM) who are ineligible for autologous stem cell transplant (ASCT) have limited first-line treatment options. Recent meta-analyses evaluating the impact of incorporating daratumumab in the backbone regimen on progression-free survival (PFS) have found mixed results in these patients. MATERIALS AND METHODS: A pooled analysis of patient-level data for ASCT-ineligible patients with HR-NDMM [ie, del(17p), t(4;14), t(14;16)] from the MAIA and ALCYONE trials; stratified by study identifier and adjusting for cytogenetic abnormality subtype, baseline performance status, International Staging System stage, myeloma type, and renal impairment; was conducted. Impact of daratumumab on PFS and rates of complete response or better (≥CR), minimal residual disease (MRD)-negative CR, very good partial response or better (≥VGPR), and overall response (ORR) was compared to control. RESULTS: Among 101 patients in the daratumumab and 89 patients in the control cohort, median follow-up was 43.7 months. Daratumumab reduced the risk of progression or death by 41% (adjusted hazard ratio for PFS [95% confidence interval (CI)] = 0.59 [0.41-0.85]) versus control. At 36 months, the estimated proportion of patients who did not progress and were still alive was 41.3% in the daratumumab and 19.9% in the control cohort. Rates of ≥CR (41.6% vs. 22.5%), MRD-negative CR (24.8% vs. 5.6%), ≥VGPR (75.2% vs. 46.1%), and ORR (92.1% vs. 74.2%) were higher for daratumumab versus control. CONCLUSION: These findings demonstrate that incorporation of daratumumab in frontline treatment regimens reduced the risk of progression or death and improved response rates among ASCT-ineligible HR-NDMM patients.

Transitioning from Once-Monthly to Once-Every-3-Months Paliperidone Palmitate Among Veterans with Schizophrenia.

PURPOSE: Compared to once-monthly paliperidone palmitate (PP1M), once-every-3-months paliperidone palmitate (PP3M) reportedly increases treatment adherence. The objective of this study was to compare treatment patterns, utilization, and costs among Veterans Health Administration (VHA) patients with schizophrenia who transitioned to PP3M versus those remaining on PP1M. PATIENTS AND METHODS: Adult VHA patients with ≥2 health care encounters (inpatient or outpatient) that included a schizophrenia diagnosis who initiated PP1M between January 1, 2015, and March 31, 2018 (identification period) were included in this exploratory retrospective cohort study. Propensity scores were used to match cases (PP1M users who transitioned to PP3M during the identification period) with controls (any patient initiating PP1M during the identification period). Data were assessed until death, health plan disenrollment, or study end. Outcomes were compared using chi-square and t-tests. RESULTS: A total of 257 eligible PP3M and 2973 eligible PP1M patients were identified among adult VHA patients; mean ages were 53.1 and 53.7 years, respectively. After propensity score matching, the PP3M and PP1M cohorts each held 111 patients. Comorbidities of patients treated with PP3M versus PP1M, respectively, included anxiety (12.5% vs 20%; standardized difference [STD] = 20.6), tobacco use (28.4% vs 43.2%; STD = 31.2), depressive disorder (26.5% vs 36.2%; STD = 21.1), and substance abuse (37.4% vs 44.2%; STD = 13.9). For the PP3M cohort, adherence (proportion of days covered ≥80%) to any antipsychotic agent was higher (78.4% vs 57.7%, P = 0.0009), and all-cause inpatient lengths of stay (LOS) were shorter (3.0 vs 8.3 days, P = 0.0354). Increased all-cause pharmacy costs with PP3M were offset by reduced all-cause medical costs, resulting in overall health care cost-neutrality. CONCLUSION: Relative to those remaining on PP1M, VHA patients with schizophrenia who transitioned to PP3M experienced improved antipsychotic medication adherence and significantly shorter all-cause inpatient LOS; costs remained neutral.

Real-World Evidence of the Clinical and Economic Impact of Long-Acting Injectable Versus Oral Antipsychotics Among Patients with Schizophrenia in the United States: A Systematic Review and Meta-Analysis.

BACKGROUND: Long-acting injectable (LAI) antipsychotics, compared with oral antipsychotics (OA), have been found to significantly improve patient outcomes, including reduced hospitalizations and emergency room (ER) admissions and increased medication adherence among adult patients with schizophrenia. In turn, the clinical benefits achieved may translate into lower economic burden. Real-world evidence of the comparative effectiveness of LAI is needed to understand the potential benefits of LAI outside of the context of clinical trials. This study aimed to provide a comprehensive synthesis of recent published real-world studies comparing healthcare utilization, costs, and adherence between patients with schizophrenia treated with LAI versus OA in the United States. METHODS: In this systematic literature review, MEDLINE® was searched for peer-reviewed, real-world studies (i.e., retrospective or pragmatic designs) published in English between January 1, 2010 and February 10, 2020. Comparative studies reporting hospitalizations, ER admissions, healthcare costs, or medication adherence (measured by proportion of days covered [PDC]) in adults with schizophrenia treated with LAI versus OA (or pre- vs post-LAI initiation) in the United States were retained. Random effects meta-analyses were conducted among eligible studies to evaluate the association of LAI versus OA use on hospitalizations, ER admissions, healthcare costs, and treatment adherence. A sensitivity analysis among the subset of studies that compared OA with paliperidone palmitate once monthly (PP1M), specifically, was conducted. RESULTS: A total of 1083 articles were identified by the electronic literature search, and two publications were manually added subsequently. Among the 57 publications meeting the inclusion criteria, 25 provided sufficient information for inclusion in the meta-analyses. Compared with patients treated with OA, patients initiated on LAI had lower odds of hospitalization (odds ratio [OR] 0.62, 95% confidence interval [CI] 0.54-0.71, n = 7), fewer hospitalizations (incidence rate ratio [IRR] [95% CI] 0.75 [0.65-0.88], n = 9), and fewer ER admissions (IRR [95% CI] 0.86 [0.77-0.97], n = 6). The initiation of LAI was associated with higher per-patient-per-year (PPPY) pharmacy costs (mean difference [MD] [95% CI] $5603 [3799-7407], n = 6), which was offset by lower PPPY medical costs (MD [95% CI] - $5404 [- 7745 to - 3064], n = 6), resulting in no significant net difference in PPPY total all-cause healthcare costs between patients treated with LAI and those treated with OA (MD [95% CI] $327 [- 1565 to 2219], n = 7). Patients initiated on LAI also had higher odds of being adherent to their medication (PDC ≥ 80%; OR [95% CI] 1.89 [1.52-2.35], n = 9). A sensitivity analysis on a subset of publications evaluating PP1M found results similar to those of the main analysis conducted at the LAI class level. CONCLUSIONS: Based on multiple studies with varying sub-types of patient populations with schizophrenia in the United States published in the last decade, this meta-analysis demonstrated that LAI antipsychotics were associated with improved medication adherence and significant clinical benefit such as reduced hospitalizations and ER admissions compared with OA. The lower medical costs offset the higher pharmacy costs, resulting in a non-significant difference in total healthcare costs. Taken together, these findings provide strong evidence on the clinical and economic benefits of LAI compared with OA for the treatment of schizophrenia in the real world.

The effect of navigation method and visual display on distance perception in a large-scale virtual building.

Immersive virtual reality (VR) technology has become a popular method for fundamental and applied spatial cognition research. One challenge researchers face is emulating walking in a large-scale virtual space although the user is in fact in a small physical space. To address this, a variety of movement interfaces in VR have been proposed, from traditional joysticks to teleportation and omnidirectional treadmills. These movement methods tap into different mental processes of spatial learning during navigation, but their impacts on distance perception remain unclear. In this paper, we investigated the role of visual display, proprioception, and optic flow on distance perception in a large-scale building by manipulating four different movement methods. Eighty participants either walked in a real building, or moved through its virtual replica using one of three movement methods: VR-treadmill, VR-touchpad, and VR-teleportation. Results revealed that, first, visual display played a major role in both perceived and traversed distance estimates but did not impact environmental distance estimates. Second, proprioception and optic flow did not impact the overall accuracy of distance perception, but having only an intermittent optic flow (in the VR-teleportation movement method) impaired the precision of traversed distance estimates. In conclusion, movement method plays a significant role in distance perception but does not impact the configurational knowledge learned in a large-scale real and virtual building, and the VR-touchpad movement method provides an effective interface for navigation in VR.

Phytochemical analysis of olive flowers' hydroalcoholic extract and in vitro evaluation of tyrosinase, elastase and collagenase inhibition activity.

Olea europaea L. is historically one of the most important trees of the Mediterranean countries. Increasing scientific interest regarding its fruits, leaves and olive oil has led to the elucidation of several phytochemical and biological characteristics. However, the phytochemical and biological studies regarding olive flowers remain limited. The aim of the present study was the phytochemical characterization of olive flowers' hydroalcoholic extract from Greek variety Lianolia, the effective isolation of the major secondary metabolites and evaluation of their inhibition activity against tyrosinase, elastase and collagenase. UPLC-HRMS/MS analysis was used to investigate the chemical composition of hydroalcoholic extract resulting in the identification of sixty-three secondary metabolites witch mainly belong to phenilethanoids, triterpenoids, flavonoids and secoiridoids. The orthogonial combination of Centrifugal Partition Chromatography and preparative HPLC in the same purification process led to the isolation of nine major compounds of the extract including two triterpenic acids, two flavonoid glycosides and five secoiridoid derivatives. From them, oleofloside A and oleofloside B are new natural products. Although, the hydroalcoholic extract and isolated secoiridoids exhibited weak or no inhibition activity towards tyrosinase and elastase, they exhibit remarkable anti-collagenase activity with 2΄-ethoxyoleuropein being the most active compound.

Methods for constructing treatment episodes and impact on exposure-outcome associations.

PURPOSE: To assess the impact on exposure time and outcome misclassifications, and consequent impact on exposure-outcome associations from treatment episode construction. We investigated the dosage assumptions of 1 unit per day, and 1 DDD per day, versus actual prescribed dosage under different handling of gaps and overlaps of prescriptions. METHODS: Data on mirtazapine and citalopram exposure (years 2006-2014) from the Swedish Prescribed Drug register were used. Via a within individuals design we compared method A, based on actual dosage, with methods B and C based on 1 unit of drug per day and 1 DDD per day assumptions, respectively, including consideration of gaps and overlaps. Four outcomes were used, hospitalizations and outpatient visits for all and for psychiatric causes. RESULTS: Relative to method A, both alternative methods lead to misclassification of exposure time. With regard to outcome misclassifications, method B overestimates the effect of the exposure on the outcome in 77% and 100% of exposure definition comparisons for mirtazapine and citalopram respectively, while 23% of the comparisons for mirtazapine results in underestimation of exposure-outcome associations. Conversely, treatment episodes based on DDD (method C) result in underestimation of the exposure-outcome association in 100% and 87.5% of exposure definition comparisons for mirtazapine and citalopram respectively, while 12.5% of the comparisons for citalopram results in overestimation of the exposure-outcome associations. CONCLUSIONS: The study provides results that have consistent clinical relevance. We have showed that a non-accurate construction of exposure time may lead to errors on outcome detection during exposed time, and consequently affect conclusions on safety or efficacy profile of a treatment.

Οlive tree blossom polyphenolic extracts exert antioxidant and antimutagenic activities in vitro and in various cell lines.

Olive oil has held a prominent place in the Mediterranean diet since ancient times due to its beneficial effects on human health thus, becoming the subject of great scientific interest. Although numerous studies have examined the biological action of olive and olive oil extracts, the literature lacks studies investigating the putative antioxidant capacity of olive tree flower extracts. Given that olive tree flowers are actually by-products of the olive oil production process with high waste burden for the environment, it becomes evident that their exploitation could increase their added value. Therefore, in this study the potential antioxidant action of four olive flower extracts was investigated. All the extracts exerted potent antioxidant activity as indicated using the DPPH• and ABTS•+ assays, as well as antigenotoxic and antimutagenic properties, identified by the results of the plasmid relaxation assay and the Ames test, respectively. Furthermore, the extracts also improved redox status of four cell lines (i.e., EA.hy926, C2C12, HeLa, and HepG2) enhancing reduced glutathione and reducing reactive oxygen species levels using flow cytometry. Taking into account that during olive tree cultivation a considerable amount of olive flowers is generated, the waste burden is high and the management is difficult. Given the optimistic findings of the present study, we believe that the flower-derived extracts may have high added value since they could be used as antioxidants or as foodstuff, food additives and functional food constituents.

Cardiovascular Risk Factors and Secondary Events Among Acute and Chronic Stable Myocardial Infarction Patients: Findings from a Managed Care Database.

INTRODUCTION: Long-term risk for recurrent cardiovascular events among myocardial infarction (MI) patients in the acute versus chronic stable phase is not well characterized. This study was conducted to evaluate risk factors associated with all-cause mortality and cardiovascular (CVD) morbidity and to determine the transition period from the acute to chronic stable phase of disease. METHODS: Administrative claims data from a managed care database (2007-2012) were linked to the Social Security Death Index. Kaplan-Meier curves were generated over a 3-year period. The association between risk factors and clinical endpoints was assessed using Cox proportional hazard models. Poisson models estimated the 'transition time' from acute to chronic phase of disease. RESULTS: On average, recurrent cardiovascular event rates were higher among acute MI patients in comparison to the chronic MI patients during the first 3 months of follow-up. Over the 3-year follow-up period, survival curves became parallel and for some outcomes (i.e., acute myocardial infarction and bleeding events), were not statistically significantly different between the two groups. In both the acute and chronic MI cohorts, diabetes, heart failure, and renal disease were consistently statistically significant and positively associated with greater risk of death and ischemic events. PAD was consistently associated with increased risk among the chronic cohort and composite endpoints among the acute patients. CONCLUSIONS: Greater understanding of differences in the CVD risk profiles and the transition from acute to chronic stable phase may help identify high-risk patients and inform clinical risk stratification and long-term disease management in MI patients. FUNDING: Merck & Co., Inc., Kenilworth, NJ, USA.

Heart versus head: Differential bodily feedback causally alters economic decision-making.

Metaphorically, altruistic acts, such as monetary donations, are said to be driven by the heart, whereas sound financial investments are guided by reason, embodied by the head. In a unique experiment, we tested the effects of these bodily metaphors using biofeedback and an incentivized economic decision-making paradigm. Participants played a repeated investment game with a simulated partner, alternating between tactical investor and altruistic investee. When making decisions, participants received counterbalanced visual feedback from their own or a simulated partner's heart or head, as well as no feedback. As investor, participants transferred a greater proportion of their endowments when exposed to visual feedback from their own head than to feedback from their own heart or no feedback at all. These effects were not observed when the source of the feedback was the simulated partner. As investee, heart feedback predicted greater altruistic returns than head or no feedback, but this effect did not differ based on source (own vs partner). Consistent with a dual-process framework, we suggest that people may be encouraged to invest more or be more altruistic when receiving bodily feedback from conceptually diametric sources.

Association of Osteoporosis Medication Use After Hip Fracture With Prevention of Subsequent Nonvertebral Fractures: An Instrumental Variable Analysis.

Importance: Osteoporosis medication treatment is recommended after hip fracture, yet contemporary estimates of rates of initiation and clinical benefit in the patient population receiving routine care are not well documented. Objectives: To report osteoporosis treatment initiation rates between January 1, 2004, and September 30, 2015, and to estimate the risk reduction in subsequent nonvertebral fractures associated with treatment initiation in patients with hip fracture. Design, Setting, and Participants: In this cohort study, data from a commercial insurance claims database from the United States were analyzed. Patients 50 years and older who had a hip fracture and were not receiving treatment with osteoporosis medications before their fracture were included. Exposure: Prescription dispensing of an osteoporosis medication within 180 days of a hip fracture hospitalization. Main Outcomes and Measures: Each initiation episode was matched with 10 nonuse episodes on person-time after the index hip fracture event to preclude immortal time bias and followed up for the outcome of nonvertebral fracture until change in exposure or a censoring event. An instrumental variable analysis using 2-stage residual inclusion method was conducted using calendar year, specialist access, geographical variation in prescribing patterns, and hospital preference. Results: Among 97 169 patients with a hip fracture identified, the mean (SD) age was 80.2 (10.8) years, and 64 164 (66.0%) were women. A continuous decline over the study years was observed in osteoporosis medication initiation rates from 9.8% (95% CI, 9.0%-10.6%) in 2004 to 3.3% (95% CI, 2.9%-3.8%) in 2015. In the effectiveness analyses, the hospital preference instrumental variable had a stronger association with treatment (pseudo R2 = 0.20) than the other 3 instrumental variables (specialist access: pseudo R2 = 0.04; calendar year: pseudo R2 = 0.05; and geographic variation: pseudo R2 = 0.07). Instrumental variable analysis with hospital preference suggested a rate difference of 4.2 events (95% CI, 1.1-7.3) per 100 person-years in subsequent fractures associated with osteoporosis treatment initiation compared with nonuse in an additive hazard model. Conclusions and Relevance: Low rates of osteoporosis treatment initiation after a hip fracture in recent years were observed. Clinically meaningful reduction in subsequent nonvertebral fracture rates associated with treatment suggests that improving prescriber adherence to guidelines and patient adherence to prescribed regimens may result in notable public health benefit.

Correction to: The Aging Urban Brain: Analyzing Outdoor Physical Activity Using the Emotiv Affectiv Suite in Older People.

Please note that the legend to Fig. 1 has been modified since this article was originally published, and also that in Tables 2, 3 and 4, R[2] was corrected to (the now correct) R squared.

Variation in adherence to medications across the healthcare system in two comparative effectiveness research cohorts.

AIM: To assess heterogeneity in adherence to medications in two example comparative effectiveness research studies. PATIENTS & METHODS: We analyzed data from commercially insured patients initiating a statin or anticoagulant during 2005-2012. We calculated the cross-validated R2 from a series of hierarchical linear models to assess variation in 1-year adherence. RESULTS: There was less heterogeneity in adherence in the statin cohort compared with the anticoagulant cohort, where patient characteristics explained 7.2% of variation in adherence, and adding therapy and provider characteristics increased the proportion of variation explained to 8.0 and 8.5%, cumulatively. Random effects provided essentially no explanatory power, even in the statin cohort with large numbers of patients clustered within each pharmacy, prescriber and provider. CONCLUSION: The dependence of adherence on the healthcare system was stronger when the healthcare system influenced treatment choice and patient access to medication and when indications for treatment were strong.

The Aging Urban Brain: Analyzing Outdoor Physical Activity Using the Emotiv Affectiv Suite in Older People.

This research directly assesses older people's neural activation in response to a changing urban environment while walking, as measured by electroencephalography (EEG). The study builds on previous research that shows changes in cortical activity while moving through different urban settings. The current study extends this methodology to explore previously unstudied outcomes in older people aged 65 years or more (n = 95). Participants were recruited to walk one of six scenarios pairing urban busy (a commercial street with traffic), urban quiet (a residential street) and urban green (a public park) spaces in a counterbalanced design, wearing a mobile Emotiv EEG headset to record real-time neural responses to place. Each walk lasted around 15 min and was undertaken at the pace of the participant. We report on the outputs for these responses derived from the Emotiv Affectiv Suite software, which creates emotional parameters ('excitement', 'frustration', 'engagement' and 'meditation') with a real-time value assigned to them. The six walking scenarios were compared using a form of high dimensional correlated component regression (CCR) on difference data, capturing the change between one setting and another. The results showed that levels of 'engagement' were higher in the urban green space compared to those of the urban busy and urban quiet spaces, whereas levels of 'excitement' were higher in the urban busy environment compared with those of the urban green space and quiet urban space. In both cases, this effect is shown regardless of the order of exposure to these different environments. These results suggest that there are neural signatures associated with the experience of different urban spaces which may reflect the older age of the sample as well as the condition of the spaces themselves. The urban green space appears to have a restorative effect on this group of older adults.